White Paper

Title: Filter Validation Guidelines

Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 1 of 9

Purpose
The purpose of this document is to provide general guidelines for validating a filter to be
used with a particular dissolution method.

Definition(s)
Control is a sample of known concentration. It should include all excipients present in a
normal sample.
Standard is a solution of known concentration of the API. The solution should not include
any excipients.
Sample is a mixture collected from a dissolution vessel. The concentration of a sample is
initially unknown and must be calculated using a standard.

In-Line Syringe Filter refers to filters typically installed on the end of a syringe using a
luer-lock fitting.

(Sample Probe) Tip Filter refers to filters that are placed on the tips of sample probes.

Detail
All dissolution methods require filtration. Filtration removes particles from the media and
stops the dissolution process in the filtered sample. This makes choosing a filter a critical part
of developing a dissolution method. Showing scientific justification for use of a given filter is a
requirement for GLP/GMP.

A filter validation process should look at the following:

• Efficiency – Does the filter remove enough particles to prevent further dissolution of
the sample?

• Leachability – Does the filter add any components to the sample as it is filtered?
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 2 of 9

• Rinse Volume Test/Adsorption – How much of a rinse does the filter need to
ensure the sample is the same concentration as what is present in the vessel?

If an automated system is used, and filters will be reused for samples, the following
should also be evaluated:
• Rinse Volume – How much media is required to rinse the filter in order to ensure the
sample is representative of what is in the dissolution vessel?
• Reuse – How many times can a filter be reused without it clogging or affecting the
concentration of the sample?
• Tip Filter – Should a tip filter be used in order to preserve the life of the in-line filter?
The tip filter must be validated with the in-line filter.
Each step of the process should be documented so that justification for each point can be
shown. When performing testing, it is recommended to perform evaluations in triplicate (three
times for each filter type).
1. Choose a filter material: The filter material should be chemically compatible with
the API, excipients, and dissolution media. At the beginning of the process it is best
to pick multiple candidates.
2. Choose a pore size: Pore size should be based largely on the requirements of the
analytical method.
a. UV spectrophotometry usually requires at least 10 micron filters.
b. HPLC typically requires 0.45 micron filters to avoid blocking or damaging the
column.
c. UHPLC (UPLC™) typically requires 0.2 micron filters to avoid damage to the
columns.
3. Select at least 2 manufacturers: Selecting more than 1 manufacturer allows for
two advantages.
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 3 of 9

a. If there is a difference in the filter performance, it will show which manufacturer is

superior for the method.

b. If the filter performance is the same, then it provides a backup filter to be used in
case there is a shortage of the primary filter.
Some filter manufacturers offer membrane filters with a built-in pre-filter. The pre-filter is
typically a material with a larger pore size (5 micron) which can filter out larger particles without
becoming clogged. This allows the membrane filter to be used primarily for smaller particles,
which in turn extends filter life. Use of a tip filter on the end of a sample probe would fulfill the
same function as a built-in pre-filter; however, it should be validated with the in-line syringe
filters.
4. Efficiency Test: This test should ensure that the dissolution process is being
stopped by removing all the particles from the sample. The test should be run with a
control at roughly 50% dissolved.
a. Pull 3 aliquots as close to simultaneous as possible.
b. Filter each of the aliquots as soon as they are pulled.
c. Analyze the first aliquot immediately.
d. Ultrasonicate the second aliquot for 5-10 minutes to attempt to dissolve any
particles the filter did not remove. Then analyze the second aliquot.
a. Ultrasonicate the third aliquot for 10-15 min to attempt to dissolve any particles
the filter did not remove. Then analyze the third aliquot.

Pass Fail

Each aliquot shows a The second and/or third

Efficiency Test
nearly identical aliquot(s) show
concentration. significantly higher
concentrations than the
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 4 of 9

first.

5. Leachability Test: This test should help ensure the filter is not adding material to
the sample, which may interfere with the results.
a. Prepare a suitable volume of dissolution media for filtering.
b. Collect 3 separate aliquots of the dissolution media each using a different filter of
the same type. These will be your filtered blank samples.
c. Prepare a standard using the dissolution media.
d. Collect 3 separate aliquots of the standard, each using a different filter of the
same type.
e. Analyze the 3 filtered blanks, and 3 filtered standards against one unfiltered
blank and one unfiltered standard.

Leachability Test Pass Fail

The concentration of the The filtered blanks show

unfiltered blank is nearly a significantly higher
Blank
identical to the filtered reading than the
blanks. unfiltered blank.

The concentration of the The filtered standard

unfiltered standard is shows a higher reading
Standard
nearly identical to the than the unfiltered
filtered standards. standard.

6. Rinse Volume Test: While the leachability test is done to ensure that nothing is
being added to the sample from the filter, the rinse volume test is to ensure that the
process of filtering does not affect the concentration of the sample. Filters often
must be rinsed with a minimum volume in order to saturate the membrane with the
API.
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 5 of 9

NOTE: This test also fulfills the adsorption test of the filter validation.
a. Prepare a standard at lowest expected concentration for the dissolution test (e.g.,
the first sample time point).
b. Manual Sampling
i. Using a 10 mL or larger syringe, fill the syringe with the standard.
ii. Dispense 1 mL aliquots into test tubes or vials for analysis.
iii. Analyze each aliquot. When the results match the concentration of the
standard, the minimum rinse volume for the filter has been determined.

c. Automated Sampling
i. Determine the empty tubing volume.
ii. Prime the lines with a blank solution (20 mL for most samplers).

iii. Wipe off probes and move them to the standard solution.
iv. Rinse with the volume determined in step 6.c.i.
v. Collect a sample.
vi. Wipe off the probes and move them to the blank solution.
vii. Prime the lines with blank solution again to remove the standard from the
lines.
viii. Repeat steps 6ciii through 6.c.vii, increasing the volume in step 6.c.iv by 1 mL
each time.
ix. Analyze each aliquot. When the results match the concentration of the
standard, the minimum rinse volume for the filter and sampler has been
determined.
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 6 of 9

Pass Fail

The concentration of the The concentration of the

Rinse Volume Test filtered samples is nearly filtered samples is
identical to the significantly below the
concentration of the concentration of the
standard. standard.

7. Filter Reuse (Stage 1): Reusing filters is an excellent way to cut costs; however,
the user must ensure that the reuse has been scientifically shown not to affect
dissolution results.
Warning: It is not permissible to reuse filters for different vessels or different
dissolution testers. Reused filters should be reused on the same tester and
vessel. Never reuse a filter for multiple dissolution tests.
a. The first stage of testing filter reuse is to ensure that sample concentrations are
not affected if a filter is used multiple times.
b. Prepare 3 standards at 10%, 50%, and 100% concentrations.
c. Using the same filter for each standard, collect an aliquot of the 10%, 50%, and
100% standards. Ensure the rinse volume is adequate by performing the rinse
volume test (step 6) prior to running this test.
d. Analyze each aliquot and ensure the results match with the standard.
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 7 of 9

Filter Reuse (Stage 1) Pass Fail

The concentration of the

The concentration is
filtered samples is nearly
significantly lower than
10% identical to the
the standard. Recheck
concentration of the
rinse volume.
standard.

The concentration of the

The concentration is
filtered samples is nearly
significantly lower than
50% identical to the
the standard. Recheck
concentration of the
rinse volume.
standard.

The concentration of the

The concentration is
filtered samples is nearly
significantly lower than
100% identical to the
the standard. Recheck
concentration of the
rinse volume.
standard.

8. Filter Reuse (Stage 2): Assuming the filter passed the first stage of the reuse test,
the next test is a mechanical check to see when a filter will clog due to particles.
NOTE: Tip filters will remove any larger particles before they can reach the filter. In
many cases, this will greatly extend the mechanical life of the filter. Tip filters should
be validated as part of the same process as the in-line filters.
a. Prepare a dissolved sample in a dissolution vessel at 100% dissolved.
b. Pump the unfiltered sample through a filter until the filter clogs. It is
recommended to evaluate 6-8 filters to account for any manufacturing
differences.
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 8 of 9

i. If sampling manually, when the syringe becomes twice as hard to push

through the filter, the filter should be considered clogged. Refill the syringe
as necessary while testing.
ii. Using the transfer command of the AutoPlus, observe the system until the
system clogs. This can be determined by listening for a rapid clicking as the
valves are forced open by the back pressure in the system.
c. Determine the lowest volume that caused a filter to clog. It is recommended to
subtract 20% from the lowest volume as a measure for how much sample can
pass through a filter safely.
i. If performing validation on an automated system, calculate the total volume
pumped through the filter at each sample point (rinse w/ filter + sample
collection) to determine how many times the filter can be reused.
d. Repeat step 8.b with the reuse specification determined from step 8.c. The test
should complete without any need to replace filters. If a filter clogs, reduce the
number of times it is reused and repeat step 8.c.

Pass Fail

A filter clogs prior to the

point determined in step
The test is completed
Filter Reuse (Stage 2) 8c. Repeat the
reusing the filters the
evaluation with a lower
number of times
number of reuses or
determined in step 8.c.
lower volume of filtered
material.
White Paper
Title: Filter Validation Guidelines
Originator: John Heaney
Doc: 0002 Rev: A Date: 28 May 2014 Page: 9 of 9

Conclusions
As with any stage of dissolution method development, filter validation should be fully
documented and justified. Each step in the process should show why a filter was chosen and
why other filters were omitted.

Recommended Reading
• USP Chapter <1092> The Dissolution Procedure: Development and Validation
• Hanson Research Technical Bulletin 1001

Technical Support
If additional technical support is required, please contact Hanson Research at
www.hansonresearch.com/tsr.htm or email techsupport@hansonresearch.com.

Disclaimer
The reader must understand the following about this document:
1. This document is meant to provide guidance for those new to filter validation. This
document is not meant to cover every possibility or condition.
2. The guidelines provided in this document may not be suitable for all products.
3. Hanson Research assumes no responsibility for issues that may arise with regulatory
agencies. Always follow GMP/GLP and adhere to regulatory requirements.